Ergonarcarnines

ABSTRACT

The invention concerns novel compounds of the formula:   WHEREIN R1 is hydrogen or methyl. The one compound, ergonorcornine, is useful in inhibiting lactation, and the other compound, 1-methyl-ergonorcornine, is useful in stimulating lactation. Processes for the production of the said compounds are also disclosed.

United States Patent Guttmann et a1.

[15] 3,681,355 [4 1 Aug. 1,1972

[54] ERGONARCARNINES [73] Assignee: Sandoz Ltd.(a/k/a Sandoz AG), Basel,Switzerland [22] Filed: June 15, 1970 [21] Appl. No.: 46,480

[30] Foreign Application Priority Data June 20, 1969 Switzerland..9462/69 [52] US. Cl. ..260/268 PE, 424/261 [51] Int. Cl. ..C07d 43/20[58] Field of Search ..260/268 PE [56] References Cited UNITED STATESPATENTS 3,586,683 6/1971 Stadler ..260/268 PE 3,113,133 12/1963 Hofmannet al ..260/268 PE 3,428,639 2/1909 Stadler et a1. ..260/268 PE2,997,470 8/1901 Pioch ..260/268 PE FOREIGN PATENTS OR APPLICATIONS1,149,565 4/1969 Great Britain ..260/268 PE Primary ExaminerDonald G.Daus Attorney-Gerald D. Sharkin. Robert S. Honor, Frederick H.Weinfeldt, Richard E. Vila and Walter F. Jewell 5 7] ABSTRACT Theinvention concerns novel compounds of the formula:

CH3 CH! wherein R is hydrogen or methyl.

The one compound, ergonorcornine, is useful in inhibiting lactation, andthe other compound, l-methylergonorcornine, is useful in stimulatinglactation.

Processes for the production of the said compounds are also disclosed.

2 Claims, No Drawings ERGONARC IMPROVEMENTS IN OR RELATING TO ORGANICCOMPOUNDS The present invention relates to new heterocyclic compounds offormula I,

C H; CH!

a x H OH:

wherein R, is hydrogen or methyl. Processes for the production of thesecompounds and their salts with acids, as well as pharmaceuticalpreparations of the compounds of formula I and their acid addition saltsare also described. In accordance with the invention a. a compound offormula I or an acid addition salt thereof is obtained by condensing asalt of the compound of formula [I CH: II

in an inert solvent and in the presence of a basic condensation agent,with a reactive, functional derivative of an acid of formula III,

wherein R is as defined above, and where required converting theresulting compound of formula I into an acid addition salt, or

b. the compound of formula la H; In

is obtained by methylating the compound of formula Ib 0 O J li. T W r:

H on, C H2 in an inert solvent and in the presence of a strong base, andwhere required converting the resulting compound of formula Ia into anacid addition salt.

Reactive, functional derivatives of acids of formula III, which may beused for the condensation of the invention in accordance with section(a), are their mixed anhydrides with trifluoroacetic acid or withsulphuric acid, their acid chloride hydrochlorides or their azides. Itis likewise possible to use the addition product of an imidohalide of anN-di(lower)alkyl-substituted carboxylic acid amide, e.g., dimethylformamide or dimethyl acetamide.

The compound of formula II is employed in the form of a salt, preferablythe hydrochloride, but other mineral acid salts may likewise be used.

One preferred method of effecting the process of the invention consistsin that compounds of formula III are reacted at 20 to l0 C withtrifluoroacetic acid anhydride in an inert solvent and in the presenceof trifluoroacetic acid, and the resulting mixed anhydrides oftrifluoroacetic acid and a compound of formula III are reacted at 20 to10 C with a salt of the compound of formula II in an inert organicsolvent and in the presence of a tertiary organic base, e. g., pyridineor homologues thereof, and the reaction mixture is allowed to react fora short time at a temperature of about-l0 to 0 C.

A preferred embodiment of the process of the invention consists in thatthe compounds of formula III are employed as a mixture. For example, themixture may contain aside from lysergic acid or l-methyl-lysergic acid,isolysergic acid or l-methyl-isolysergic acid and 6-methyl-A-ergolene-8-carboxylic acid or l-methyl- 6-methyl-A-ergolene-8-carboxylic acid. A mixture of lysergic acid, isolysergicacid and 6-methyl-A -ergolene-8-carboxylic acid may be obtained directlyby saprophytic cultivation of the fungus strain NRRL 3080 of the speciesClaviceps paspali Stevens et Hall. This mixture may be dried by heatingto 150 C in a vacuum and is preferably employed in dry form.

For the production of the mixed anhydrides of compounds of formula illwith trifluoroacetic acid the ratio of the starting materials is chosensuch that l to 1.4 mols of trifluoroacetic acid anhydride and 2 mols oftrifluoroacetic acid are used for every moi of the dry mixture ofcompounds of formula III. Examples of inert solvents which may be usedare acetonitrile, dimethyl formamide, dimethyl acetarnide,propionitrile, N- methyl-pyrrolidone, methylene chloride, or mixturesthereof.

The sequence of the addition of the reagents for the production of themixed anhydrides is exchangeable. Thus, for example, the dry mixture ofcompounds of formula 111 may be suspended in one of the organic solventsmentioned above and may be dissolved in l to 5 mols, preferably about 2mols of trifluoroacetic acid, and 1.2 mols of trifluoroacetic acidanhydride may then be added, or both reagents may be simultaneouslyadded dropwise to a suspension of the compounds of formula III in theinert solvent. It is furthermore possible to exchange the sequence ofthe addition of trifluoroacetic acid and trifluoroacetic acid anhydride.

Since the resulting mixed anhydrides of compounds of formula III withtrifluoroacetic acid decompose easily, they are preferably usedimmediately in solution for the next reaction. The compound of formulaII in the form of a salt, e.g., the hydrochloride, is then immediatelyadded to this solution. The base of formula II is liberated by theaddition of a large excess of a tertiary organic base at 20 to C; thisbase reacts spontaneously with the mixture of compounds of formula Ill.If desired, the sequence of the addition of the base and the salt of thecompound of formula ll may be exchanged.

In accordance with a further embodiment, the mixed anhydrides of acidsof formula III with sulphuric acid are used and the condensation iseffected in an inert solvent, e.g., dimethyl formamide, in the presenceof a tertiary organic base, at l0 to 0 C, with a salt of the compound offormula II.

In accordance with yet a further embodiment, the acid chloridehydrochlorides of acids of formula Ill are used, and the condensation iseffected in an inert solvent, in the presence of a tertiary organic orweak inorganic base, at -l0 to 0 C, with a salt of the compound offormula II.

In accordance with another embodiment, the azides of acids of formulaIII are used and the condensation is effected in the presence of atertiary organic base, at a temperature of about 0 C to roomtemperature, in an inert solvent, with a salt of the compound of formulaII.

In accordance with yet another embodiment, a salt of the compound offormula II is reacted with a compound of formula III, in an inertsolvent and in the presence of an N-di(lower)alkyl-substituted acidamide of an aliphatic monocarboxylic acid and a chlorinating andbrominating agent, as well as an acid-binding agent.

The compound of formula la may likewise be obtained in accordance withthe invention by methylating the compound of formula Ib in the presenceof a basic condensation agent, e.g., an alkali metal alcoholate oralkali metal amide, and optionally converting the resulting methylationproduct into an acid addition salt.

One preferred method of effecting the methylation process of theinvention consists in adding metallic sodium or potassium portionwise toa solution of a lower aliphatic alcohol, e.g., ethanol, in liquidammonia, and waiting until discoloration of the solution occurs. Thecompound of formula lb is added at about 40 C while stirring well to theresulting solution of the alkali metal alcoholate, and after itsdissolution methyl iodide is added, the ammonia is removed byevaporation in a vacuum and. the residue is divided between an aqueousalkali metal carbonate solution and methylene chloride, the organicphase is washed with water, dried over sodium sulphate, and themethylene chloride is removed. For this reaction it is preferred to useabout 5 mols of an alkali metal alcoholate and approximately the sameexcess of methyl iodide for every mol of the compound of formula lb.

The compounds of formula I are useful because they possesspharmacological activity in animals. More particularly, the compoundergonorcornine is useful in inhibiting lactation as indicated by aninhibition of pseudocyesis in rats and an inhibition of lactation inrabbits. The compound lmethyl-ergonorcornine on the other hand is usefulin stimulating lactation as indicated by an inducement of pseudocyesisin rats.

For the above-mentioned uses, the dosages administered will of coursevary depending on the mode of administration and the extend of theeffect desired. However, in general, satisfactory results are obtainedfor each of the effects(one effect with the one compound and the otherwith the other compound) at daily dosages between 0.1 and 3 mg/kg testanimal body weight, conveniently given in divided doses 2 to 3 times aday or in sustained release form. For larger mammals, total dailydosages (for each of the effects) range from about 1 mg to about 15 mgof active compound, and unit dosage forms suitable for oraladministration contain between 0.3 and 15 mg of the particular compoundin association with a pharrnaceutically acceptable carrier or diluent.

The new compounds may be used as medicaments on their own or in the formof appropriate medicinal preparations for oral, enteral or parenteraladministration.

The compounds of formula I are named with trivial names in a manneranalogous to the names of other, already known ergot alkaloids, or theirnames are derived from the basic structure of formula IV.

The compound of formula IV is named ergopeptine.

The prefix l-methyl" is placed before the name in the case of thecompounds of formula 1, wherein R is methyl.

In the following examples, which illustrate the process without in anyway limiting the scope of the invention, all temperatures are indicatedin degrees Centigrade and are uncorrected.

EXAMPLE 1 Ergonorcorhine (ZB-isopropyl-S'a-n-propyl-ergopeptine) 2.68 gmillimols) of an anhydrous mixture of 40 percent of d-lysergic acid, 40percent of 6-methyl-A ergolene-S-carboxylic acid and percent ofisolysergic acid are dissolved in cc of absolute dimethyl formamide bythe addition of 2.28 g (20 millimols) of trifluoroacetic acid, and themixture is brought to a temperature of 10 while stirring. A mixture of2.52 g (12 millimols) of trifluoroacetic acid anhydride in 12 cc ofabsolute acetonitrile is added dropwise at this temperature within 5minutes, and the solution is stirred for a further 10 minutes. 1.73 g (5millimols) of (2R,5 S ,b l OaS, lObS )-2-amino-3 ,6-dioxol Ob-hydroxy-2-isopropyl-5-(propyl-l )-octahydro-8H-oxazolo 3 ,2-a]pyrrolo[2,l-c]pyrazine hydrochloride and 12 cc of pyridine aresubsequently added with strong cooling, and the reaction mixture isstirred at a temperature between 10 and 0 for a further hour. Working upis effected by diluting with 200 cc Ergonorcornine methylene chlorideand shaking thoroughly with 100 cc of a 2 N sodium carbonate solution.The aqueous phase is again extracted thrice with 100 cc amounts ofmethylene chloride. The combined organic phases are dried over sodiumsulphate and concentrated by evaporation in a vacuum. The residue ischromatographed on silica gel with ethyl acetate. Ergonorcomine, havinga MP. of l75-l77, [a] 75 (c 1.5 in pyridine), is obtained afterrecrystallization with ethyl acetate.

EXAMPLE 2 ERGONORCORNINE (2 B-isopropyl-S 'a-n-propyl-ergopeptine 37.2 g(115 millimols) of d-lysergic acid chloride hydrochloride and 20.8 g (60millimols) of (2R,5S,10 a8, 10bS)-2-arnino-3,6-dioxo-10b-hydroxy-2-isopropyl- S-(propy-l)-octahydro-8l-l-oxazolo[ 3 ,2-a]pyrrolo[ 2,l-c]pyrazine hydrochlorideare suspended in 300 cc of dimethyl formamide, and stirring is effectedat lO. 11.5 cc of anhydrous pyridine are added dropwise within 15minutes, whereby the suspension gradually dissolves. Stirring iscontinued at 25 for 90 minutes. After the addition of 60 cc of a 4 Nsodium carbonate solution, the solution is evaporated to dryness at andreduced pressure, the residue is dissolved in a mixture of 1,000 cc ofmethylene chloride/methanol (8:2) and 200 cc of a 4 N sodium carbonatesolution, and the phases are separated. The organic phase is washedthrice with 200 cc amounts of a 4 N sodium carbonate solution, thecombined aqueous phases are extracted 4 times with 500 cc amounts ofmethylene chloride/methanol (8:2), the combined organic phases are driedover sodium sulphate and animal charcoal and are evaporated to dryness.The residue is chromatographed on silica gel with ethyl acetate.Ergonorcornine, having a MP. of l-17'7, [a] 75 (c 1.5 in pyridine), isobtained after recrystallization with ethyl acetate.

EXAMPLE 3 l-Methyl-ergonorcornine( l-methyl-2 '[3-isopropyl-5'an-propyl-ergopeptine) A solution of 2 cc of absolute ethanol in 2.5 ccof absolute ether is added dropwise within 20 minutes while stirring toa solution of 0.49 g of sodium metal in cc of liquid ammonia, wherebythe initially dark blue solution is decolorized. 1.31 g of dryergonorcornine are subsequently added, stirring is effected for 5minutes until the material dissolves completely, and 1.65 g of methyliodide in 2 cc of absolute ether are added dropwise at 40 within 5minutes. After stirring for half an hour at the same temperature theclear solution is carefully heated and the ammonia is drawn off bysuction in a partial vacuum. The remaining yellow residue is dissolvedin a mixture of 50 cc of methylene chloride and 50 cc of a concentratedaqueous sodium bicarbonate solution. The organic phase is washed with anaqueous sodium bicarbonate solution and then with a 30 percent commonsalt solution. After drying the combined organic phases and removing thesolvent by distillation at 50 the residue is taken up and crystallizedin ethyl acetate, whereby an already thin layer chromatographically purel-methyl-ergonorcomine, having a decomposition point of 223, isobtained. [a] 88 (0 1.1 in pyridine).

The(2R,5S,10aS,10bS)-2-amino-3,6-dioxo-10bhydroxy-2-isopropyl-5-(propyl-l)-octahydro-8H-oxazolo[3,2-a]pyrrolo[2, 1 -c]-pyrazine hydrochloride,used as starting material, is produced as follows:

a. (3S,8aS)-1,4-dioxo-3-(propyl-l )-octahydro-pyrrolo[ l,2-a]pyrazine.

24.9 g (0.1 mol) of N-carbobenzoxy-L-proline and 13.3 g (0.1 mol) offreshly distilled L-norvaline methyl ester are dissolved in 100 cc ofethyl acetate, and 22.6 g (0.11 mols) of dicyclohexyl carbodiimide in 25cc of ethyl acetate are added dropwise at 5-l0 while stirring. Thereaction mixture is stirred at 40 for 1 hour, the precipitatingdicyclohexyl urea is filtered off and the filtrate is washed first withN hydrochloric acid and then with N ammonium hydroxide. Afterconcentrating the ethyl acetate solution, petroleum ether is added andthe N-carbobenzoxy-L-prolyl-L-norvaline methyl ester which crystallizesis filtered off. M.P. 98, [a] +8 in acetic acid.

36.2 g (0.1 mol) of Ncarbobenzoxy-L-prolyl-L-norvaline methyl ester aredissolved in 400 cc of methanol, and hydrogenation is effected with 2 gof palladium 10 percent) on active charcoal at room temperature andnormal pressure. After removing the catalyst by filtration the solventis removed in a vacuum and the oily residue is dissolved in 200 cc ofm-xylene. 40 mg of benzoic acid are added to the solution, approximately20 cc of the solvent are removed by distillation and the reactionmixture is subsequently boiled at reflux for 5 hours. After cooling thesolution is allowed to crystallize. After standing at about 0 forseveral days crystalline (3S,8aS)- l ,4-dioxo-3-(propyl)-l)-octahydro-pyrrolo[1,2-a]pyrazine is obtained. MP. 134, [a],, 1 35 -2),0 1 in ethanol.

(2R,5 S, l OaS, I bS)-2-carboxy-3 ,6-dioxo- 1 0bhydroxy-2-isopropyl-5propyl-l )-octahydro-8l-loxazolo[ 3 ,2-a]pyrro1o[ 2, l -c ]pyrazine.

78.4 g (400 millimols) of (3S,8aS)-l,4-di0xo-3-(propyl-l)-octahydro-pyrrolo[ l,2-a]pyrazine are dissolved in 200 cc ofdioxane, 144 g of N-ethyl diisopropylamine and 120 g (400 millimols) of2- benzyloxy-2-isopropyl-malonic acid chloride monoethyl ester areadded, and the mixture is heated to 70 while stirring for 3 hours. Theresulting thick mass is dissolved in 600 cc of glacial acetic acid andhydrogenation is effected in the presence of 25 g of 10 percentpalladium on charcoal at 50 and normal pressure. After the taking up ofhydrogen is complete a further g of catalyst are added and hydrogenationis continued. The catalyst is removed by filtration, the filtrate isdried at 30 and the residue is dissolved in ethyl acetate. The solutionis washed with N hydrochloric acid and subsequently with N sodiumbicarbonate solution and the organic solution is evaporated to dryness.The resulting (2R,5S, l OaS, 1 0bS)-2-ethoxycarbonyl- 3 ,6-dioxol0b-hydroxy-2-isopropy1-5-(propyl-1 )-octahydro-8H-oxazolo[ 3,2-a]-pyrrolo[ 2, l-c]pyrazine is dissolved in a mixture of 100 cc ofdioxane and 550 cc of a 2 N caustic soda solution and the solution iskept at 25 for 4 hours. After cooling to 0 the pH of the solution isadjusted to 7.5 with 4 N sulphuric acid, the solution is concentrated byevaporation to half its volume, is washed with ethyl acetate, and theaqueous phase is acidified to pH 1 with 4 N sulphuric acid and isextracted with ethyl acetate. This ethyl acetate extract is dried oversodium sulphate, is evaporated to dryness, and the residue isrecrystallized from ether. The resulting (2R,5S,l0aS,l0bS)-2-carboxy-3,6-dioxo-10bhydroxy-2-isopropyl-5-(propyl-l)-octahydro- 8l-l-oxazolo[3,2-a]pyrrolo[2,l -c]pyrazine has a M.P. ofl52l53 (decomp.), [a] +3l (c= l in dimethyl formamide).

c. (2R,5S,10aS, l0bS)-2-chloroformyl-3,-dioxolOb-hydroxy-Z-isopropyl-5-(propyl-1 )-octahydro- 8H-oxazolo[ 3,2-a]-pyrrolo[ 2, l-c]pyrazine.

27 g (130 millimols) of phosphorus pentachloride are suspended in amixture of 320 cc of anhydrous diethyl ether and 320 cc of petroleumether, the suspension is stirred at 25 for 60 minutes, is cooled to 10,34 g (100 millimols) of (2R,5S,10aS,l0bS)-2-carboxy-3 ,6-dioxol0b-hydroxy-2-isopropyl-5-( propyl- 1 octahydro-8H-oxazolo[ 3,2-a]pyrrolo[2, l -c ]pyrazine are added and the suspension is stirredat 25 for 4 hours. After filtration the crystalline mass is washed withether/petroleum ether (1:1 and dried in a vacuum in the absence ofmoisture. (2R,5S,lOaS,10bS)-2- chloroformyl-3 ,6-dioxol0b-hydroxy-2-isopropyl-5 (propyl-l )-octahydro-8l-l-oxazolo[ 3,2-a]pyrrolo[2,1- c]pyrazine, having a M.P. of l l5-1 17 (decomp.), [a]+33 in methylene chloride, is obtained. This compound is unstable and isused as rapidly as possible for the following stage of the synthesis.

When phosphorus pentabromide is used as halogenating agent thecorresponding (2R,5S,10 a8, 1 ObS )-2-bromoformyl-3 ,6-dioxo l0b-hydroxy-2- isopropyl-S-(propyl-l )-octahydro-8H-oxazolo[ 3 ,2-a]-pyrrolo[2, 1-c]pyrazine is obtained.

d. 2R,5S, l OaS, 1 ObS)-2-benzyloxycarbonylamino- 3,6-di0xo-10b-hydroxy-Z-isopropyl-S-(propyll octahydro-8H-oxazolo[ 3,2-a]pyrrolo-[ 2, l c]pyrazine.

23.5 g (67 millimols) of (2R,5S,l0aS,l0bS)-2- chloroformyl-3 ,6-dioxo- 1Ob-hydroxy-Z-isopropyl-S (propyl-l )-octahydro-8H-oxazolo[ 3,2-a]pyrrolo[ 2, 1 c]pyrazine are gradually added at -5 while stirringvigorously to a mixture of 250 cc of methylene chloride, 34 cc of waterand 11.3 g (173 millimols) of sodium azide, and the mixture is stirredfor a further 6 minutes. After separating the phases the aqueous phaseis extracted with 100 cc of methylene chloride, the combined organicphases are washed with N sodium hydrogen carbonate solution, are driedover sodium sulphate and evaporated to dryness. The residue is dissolvedin 130 cc of waterand alcohol-free chloroform, 10.3 g (96 millimols) ofbenzyl alcohol are added, the mixture is heated at reflux for minutes,is concentrated by evaporation, and the crystalline residue iscrystallized from diethyl ether. (2R,5S,l0aS,l0bS)-2-benzyloxycarbonylamino-3,6 -dioxol 0b-hydroxy-2- isopropyl-S-(propyl- 1)-octahydro-8H-oxazolo[ 3,2-a] pyrrolo[2,l-c]pyrazine, having a M.P. of205-207, [a] =+39 (c= l in pyridine), is thus obtained.

e.(2R,5S,]0aS,10bS)-2-amino-3,6-dioxo-l0bhydroxy-Z-isopropyl-S-(propyl-l)-octahydro-8H- oxazolo[ 3,2-a]pyrrolo[ 2, l -c[ pyazine hydrochloride.

495g (111 millimols) of (2R,5S,10aS,10bS)-2- benzyloxycarbonylamino-3,6-dioxol Ob-hydroxy-Z- isopropyl-S -(propyl-l )-octahydro-8H-oxazolo3,2- a]pyrrolo[2,l-c]pyrazine are dissolved in a mixture of 200 cc ofdimethyl formarnide and 500 cc of dioxane, 34 cc of a 4 N hydrochloricacid solution in dioxane and 12 g of 10 percent palladium on charcoalare added, and hydrogenation is efiected at normal pressure and roomtemperature. After the taking up of hydrogen is complete, filtration iseffected, the catalyst is washed with methylene chloride, and thefiltrate is dried. After crystallizing the residue from cc oftetrahydrofuran (2R,5S, l OaS, l ObS )-2-amino-3 ,6- dioxolOb-hydroxy-2-is0propyl-5-(propyl- 1 )-octabrydro-8H-oxazolo[3,2-a]pyrrolo[ 2, l-cl-pyrazine hydrochloride, having a M.P. of 142(decomp.), [a] +29 (c= 2 in trifluoroacetic acid), is obtained.

The d-2-benzyloxy-Z-isopropyl-malonic acid chloride monoethyl ester,used as starting material in stage (b), may be produced as follows:

a. 2-Benzyloxy-2-isopropyl-malonic acid diethyl ester.

133 g (0.5 mols) of 2-benzyloxy-malonic acid diethyl ester and g (0.6mols) of diisopropyl sulphate are mixed, and a sodium alcoholatesolution prepared from 15 g of sodium and 300 cc of absolute ethanol isadded dropwise within 90 minutes while stirring and slightly cooling (toabout 3545). The reaction mixture is subsequently stirred at 45 for 2hours and then at 60 for 1 hour. The reaction mixture is cooled to roomtemperature, is made neutral with glacial acetic acid, and 1.5 liters ofwater are added. Working up is effected by extracting several times withether, washing the combined ethereal phases with a dilute aqueous sodiumcarbonate solution and subsequently with water. The ethereal extractsare dried over sodium sulphate and the solvent is removed byevaporation. The remaining yellow oil is distilled at 0.1 mm of Hg and abath temperature of 200 for purposes of purification.

b. 2-Benzyloxy-2-isopropyl-malonic acid monoethyl ester.

924 g (3.0 millimols) of 2-benzyloxy-2-isopropylmalonic acid diethylester are dissolved in 2400 cc of ethanol, 4,400 cc (6.15 millimols) ofa 1.40 N solution of potassium hydroxide in ethanol are added whilestirring, and the reaction mixture is stirred at 25 for 16 hours. Afterthe addition of 3,000 g of ice the pH of the reaction mixture isadjusted to 8.0 with about 120 cc of concentrated phosphoric acid, andthe ethanol is removed in a vacuum at 3040. After the addition of 3,000cc of distilled water the pH of the reaction mixture is adjusted to 8 to9 with about 180 cc of 4 N caustic soda solution. The resulting lightyellow solution is extracted thrice with 1,000 cc amounts of ether,whereby the ethereal extract is counterextracted each time with 60 ccamounts of a 10 percent sodium bicarbonate solution, and the combinedsodium bicarbonate extracts are added to the aqueous solution. Thealkaline, aqueous solution is cooled to -5, is covered with a layer of3,000 cc of ether and is then slowly acidified to pH 2 with about 840 ccof concentrated phosphoric acid while stirring vigorously. The twophases are separated and the aqueous phase is again extracted twice with600 cc amounts of ether. The com bined ether solutions are washed with600 cc amounts of water (4 to 5 times) until the wash water has a pHvalue of 4, whereby the wash water is extracted back each time with 100cc of ether. The combined ethereal solutions are washed twice with 600cc amounts of a 30 percent sodium chloride solution, are dried oversodium sulphate, filtered off, concentrated and dried in a high vacuumuntil a constant weight is obtained. A viscous, slightly yellowish oilis obtained, which is homogeneous in accordance with the thin layerchromatogram (silica gel), eluant: methanol and chloroform/methanol(7:3). n 1.4988.

c. R(+)-2-benzyloxy-Z-isopropyl-malonic acid monoethyl ester.

1,460 g (8.83 mols) of l-pseudoephedrine dried at 50 in a high vacuumfor 16 hours are added to a solution of 2,330 g (8.32 mols) of racemic2-benzyloxy-2- isopropyl-malonic acid monoethyl ester in liters of etherover sodium wire while stirring vigorously and in the absence ofmoisture, seeding is effected with 1 g of the diastereoisorner formedfrom l-pseudoephedrine and S()-2-benzyloxy-2-isopropyl-malonic acidmonoethyl ester, and the mixture is allowed to stand at 0 for 2 days. Acrystalline crust is formed, which is decanted and washed with 1,000 ccof anhydrous ether. 3,000 g of ice are added to the ethereal solution,and the solution is carefully acidified with concentrated phosphoricacid while stirring vigorously. After separating the phases the aqueousphase is again extracted thrice with 1,000 cc amounts of ether. Thecombined ethereal phases are then washed five times with 2,000 ccamounts of water, and the wash water is extracted each time with 500 ccamounts of ether, which are added to the combined ether phase. The pH ofthe last wash water should amount to about 4. After washing the etherealphase with 2,000 cc of a 30 perum sulphate, and the solution is dried. Aviscous oily residue is obtained, which is dried at 30 in a high vacuumfor 16 hours on a rotary evaporator with slow rotation, until a constantweight is obtained. The resulting oil, enriched withR(+)-2-benzyloxy-2-isopropylmalonic acid monoethyl ester, is dissolvedin 12 liters of ether over sodium wire, and 1,127 g (6.81 mols) ofd-pseudoephedrine, dried in a high vacuum at 50 for 16 hours, are addedwhile stirring vigorously. After dissolution (2 to 3 minutes) andseeding with the diastereoisorner formed from d-pseudoephedrine andR(+)-2-benzyloxy-2-isopropyl-malonic acid ethyl ester the solution isallowed to stand at 0 for 2 days. The. crystalline crust is decanted andthe crystalline mass is washed 5 times with 1,000 cc amounts ofanhydrous ether. The resulting diastereoisorner formed fromR(+)-2-benzyloxy-2-isopropy1-malonic acid monoethyl ester andd-pseudoephedrine is suspended in 5,000 cc of ether, 3,000 g of ice and685 cc of concentrated hos horic cid are adde wi stirrin the bases reEepaiiated, the aqueous p ase is extra%ted tlirice with 1,000 cc amountsof ether, and the combined ethereal solutions are washed 5 times with1,000 cc amounts of water, and are counterwashed each time with 300 ccamounts of ether. The pH of the last wash water should amount to 4. Thecombined ethereal solutions are washed with 1,000 cc of a 30 percentcommon salt solution, are dried over sodium sulphate, evaporated todryness and dried in a high vacuum on a rotary evaporator with slowrotation. The residue is homogeneous in accordance with the thin layerchromatogram on silica gel in chloroform/methanol (7:3) (developmentwith potassium permanganate). [a],, +8.2 (c= 5.0 in ethanol).

d. S(+)-2-benzyloxy-2-isopropyl-malonic chloride monoethyl ester.

981 g (3.5 millimols) of R(+)-2-benZyloxy-2- isopropyl-malonic acidmonoethyl ester are dissolved in 1,500 cc of methylene chloride, thesolution is cooled to -20, a solution of 560 cc (3.85 millimols) ofdimethyl forrnamide in 530 cc of methylene chloride is added, and asolution of 328 cc (4.55 millimols) of thionyl chloride in 328 cc ofmethylene chloride is subsequently added dropwise while stirringvigorously, the cooling bath is removed and the reaction mixture isstirred at 25 for a further 16 hours. The methylene chloride is removedby evaporation in a vacuum at 30 and the bath temperature issubsequently raised from 30 to As soon as distillation stops, this iscontinued in a high vacuum at a bath temperature of 70 for a further 3hours, whereby a white byproduct which reacts violently with water,sublimates. A heterogeneous, dark brown mixture is obtained, which iskept over night at 15. A dark crystalline mass separates. The liquid isdecanted in the absence of moisture and is distilled twice withoutfractionation at a bath temperature of in a high vacuum and in theabsence of moisture, whereby each distillation should not exceed 3 hours(distillation temperature l20/0.3 mm of Hg and l05/0.05 mm of Hg). Alight yellowish liquid is thus obtained. n 1.5008, [ab +51.3 (c 5.0 inbenzene).

What is claimed is:

1. Ergonorcornine.

2. l-Methyl-ergonorcornine.

acid

Disclaimer 3,681,355.-Steph0m Gutt'ma'rm, Allschwil, and Rene H uhuem'n,Reinach Basel- Land, both of Switzerland. ERGONARCARNINES. Patent datedAug. 1, 1972. Disclaimer filed May 22, 1972, by the assignee, SandoeLtd. (also known as Sandoz A.G.)

4 Hereby disclaims the portion 6f the term of the patent subsequent toMay 30,1989.

[Official Gazette September 11 1.973.]

2. 1-Methyl-ergonorcornine.